EP1763363B1 - Pharmazeutische zusammensetzungen, die diaminooxidase enthalten - Google Patents

Pharmazeutische zusammensetzungen, die diaminooxidase enthalten Download PDF

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Publication number
EP1763363B1
EP1763363B1 EP05758617A EP05758617A EP1763363B1 EP 1763363 B1 EP1763363 B1 EP 1763363B1 EP 05758617 A EP05758617 A EP 05758617A EP 05758617 A EP05758617 A EP 05758617A EP 1763363 B1 EP1763363 B1 EP 1763363B1
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Prior art keywords
diaminooxidase
dao
histamine
medicament
gastric
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English (en)
French (fr)
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EP1763363A1 (de
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Albert Missbichler
Franz Gabor
Herwig Reichl
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Sciotec Diagnostic Technologies GmbH
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Priority to EP07101239A priority Critical patent/EP1782824B1/de
Priority to SI200530749T priority patent/SI1763363T1/sl
Priority to AT05758617T priority patent/ATE432710T1/de
Priority to PL05758617T priority patent/PL1763363T3/pl
Publication of EP1763363A1 publication Critical patent/EP1763363A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/06—Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/262—Cellulose; Derivatives thereof, e.g. ethers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y104/00—Oxidoreductases acting on the CH-NH2 group of donors (1.4)
    • C12Y104/03—Oxidoreductases acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
    • C12Y104/03006—Amine oxidase (copper-containing)(1.4.3.6)

Definitions

  • the present invention relates to compositions for the treatment or prevention of histamine-induced diseases and disease states.
  • Histamine (1H-imidazole-4-ethylamine) is produced by enzymatic decarboxylation of histidine and is thus a basic biogenic amine with a molecular weight of 111 Da.
  • histamine In the organism histamine is practically ubiquitous. It is produced by humans themselves and stored in the metachromatic granules of mast cells and basophilic leukocytes in an inactive form, where it is available for immediate release. The highest histamine concentrations are measured in the lungs. After release, histamine is a potent potent mediator of a variety of pyhsiological and pathophysiological processes, often interacting with cytokines.
  • histamine can also enter the body from the outside, on the one hand by inhalation or by the oral route, for example by the intake of histamine-containing foods such as cheese, wine, canned fish and sauerkraut.
  • DAO diaminooxidase
  • NMT histamine N-methyltransferase
  • DAO removes histamine, which has been absorbed through the food into the gastrointestinal tract, for example, and NMT controls the histaminergic signaling in the nervous system (Kitanaka et al., 2002).
  • DAO The main task of the DAO is to prevent food-borne histamine from entering the bloodstream. If this protective mechanism fails, it can also lead to anaphylactic shock in extreme cases (Taylor 1986, Nilsson et al., 1996). DAO is a secretory protein and thus works extracellularly, whereas N-methyltransferase is exclusively active in the cytosol (Küfner et al., 2001).
  • the native DAO which in addition to histamine can degrade other biogenic amines, such as putrescine, spermidine, and cadaverine, and is derived from, for example, porcine kidney, is a homodimeric copper-containing glycoprotein in which the subunits are linked by disulfide bridges.
  • DAO has one Molecular weight of about 182 kDa (Kluetz and Schmidt 1997, Rinaldi et al., 1982) and a carbohydrate content of about 11% (Shah and Ali 1988).
  • Characteristic of the copper-containing amino oxidases is an active site topachinone that results from post-translational modification of a conserved tyrosine residue (James et al., 1990, James et al., 1992, Mu et al., 1992).
  • DAO is found mainly in the small intestine, liver, kidneys, and blood in white blood cells.
  • DAO is additionally formed in the placenta.
  • Pregnant women have about 500 to 1000 times higher blood DAO levels than non-pregnant women.
  • DAO is produced continuously and excreted in the intestinal lumen.
  • histamine-rich food is therefore already largely released from histamine in the intestine. The remaining histamine is degraded when passing through the intestinal mucosa of the DAO located there. Histamine is broken down into imidazole acetaldehyde and further into imidazole-acetoacetic acid.
  • DAO The co-factors of DAO are 6-hydroxydopa and probably pyridoxal phosphate, the vitamin B6.
  • DAO is a sensitive enzyme that can be inhibited by various substances, such as other biogenic amines, alcohol and its breakdown product acetaldehyde and various drugs. In neuronal tissue so far no DAO activity could be detected.
  • DAO inhibitors are acriflavines, diazepam, N-methyl-N-formylhydrazine, b-aminopropionitriles, dimaprit, O-methylhydroxylamine, agmantine, ethanol (10%), pargyline, aldomet, furosemide, phenamil, amiloride, guanabenz, phenelzine, Aminoguanidine, guanfacine, phenformin, amitryptiline, guanidine, phenyprazine, amodiaquine, haloperidol, promethiazine, anserine, hyamine 1622, propranolol, aziridinylalkylamine, hydroxychloroquine, B1 pyrimidine, hydroxylamine, quinacrine
  • WO 02/43745 discloses the systemic use of DAO of plant origin for the treatment of histamine-mediated diseases.
  • the administration of DAO or of enzymes generally isolated directly from plants is very problematic due to the frequent occurrence of allergens in plants, especially in view of the fact that the WO 02/43745 legumes have a strong allergenic potential.
  • the object of the present invention is to provide compositions for the treatment and prevention of histamine-induced diseases and disease states which reduce the side effects of the marketed products include cortisone, do not have and eliminate the disadvantages of the above-mentioned prior art.
  • a further object of the present invention is to increase the concentration of active diaminooxidase in the body, in particular in the intestinal tract, of an individual in order thereby to support or facilitate the breakdown of histamine, in particular exogenously (eg by food).
  • the present invention relates to pharmaceutical compositions for the treatment of histamine-induced diseases comprising diaminooxidase, wherein the composition is in a dosage form for oral or peroral administration, in a hapenic acid protected dosage form.
  • the diaminooxidase is present in the compositions of the invention substantially in its active form, i. that enzymes which, for example, have no copper in their prosthetic group and do not show at least wild-type activity, are not suitable for the uses according to the invention.
  • the pharmaceutical composition of the present invention has a dosage form which allows administration selected from the group consisting of orally and perorally.
  • oral and peroral administration of the composition according to the invention it is possible to bring DAO into the gastrointestinal tract of an individual and there successfully to inhibit histamine-induced diseases by degradation of histamine or treat.
  • the range of action of the DAO is limited primarily to the intestinal tract, since the high acidity in the stomach has a negative effect on the activity of DAO. Therefore, it is required for oral or peroral administration to protect DAO from gastric acid until reaching the intestinal tract.
  • the pharmaceutical composition is provided in a dosage form selected from the group consisting of enteric-coated pellet, tablets and capsules.
  • a dosage form selected from the group consisting of enteric-coated pellet, tablets and capsules.
  • pharmaceutical compositions containing DAO also contain other ingredients that are used to stabilize the enzyme on the one hand and to bring the enzyme into the appropriate galenic form on the other hand.
  • DAO may also be co-administered with other pharmaceutically active agents in a single dosage form or separately, unless the enzyme is inhibited by any of these agents to the extent that activity of the enzyme does not produce the desired effect.
  • DAO Dietary supplement composition
  • a Dietary supplement composition adapted as an enteric-coated pellet, drop or infusion.
  • DDM Dietary supplement composition
  • the oral administration of DAO by means of a food, dietary supplement or dietetic food requires that this enzyme reaches the area of the body in which it is to have its effect. Since histamine plays an important role in the intestinal tract, it is necessary that DAO be adapted in such a way that it can pass undisturbed the strongly acidic stomach.
  • the DAO is worked up as an enteric-coated pellet.
  • DAO is irreversibly damaged at a pH below 3 (in the stomach, the pH is between pH 2 and 4), it is necessary to transport the DAO through the stomach into the intestinal tract that the DAO in a corresponding dosage form (Pharmaceutical or dietary supplement composition or dietary food) is provided.
  • capsules for example gelatin capsules
  • enteric-coated pellets have proved to be particularly advantageous. It is advantageous if the effect of DAO occurs at the latest 15, preferably at the latest 20, in particular at the latest 30 minutes after administration.
  • “gastroresistant” refers to the property of the pellet which contains an active substance (eg DAO) which has comparable properties as gastric juice (eg acid) to a gastric juice or a solution for a certain period of at least 10, preferably at least 20 even more preferably at least 30, especially at least 60, minutes such that the active substance has an activity loss of not more than 50%, preferably not more than 40%, more preferably not more than 30%, most preferably not more than 20%, in particular maximum 10%, learns.
  • an active substance eg DAO
  • gastric juice eg acid
  • the pellet according to the invention sets in the intestine after 20 minutes, in particular after 30 minutes, at least 60%, in particular at least 80%, of the DAO activity which was used to formulate the pellets.
  • Gastroresistant pellets are pellets coated with an enteric coating that dissolves at a pH similar to that found in the intestinal tract. Ie such Thus, coatings preferably dissolve at a pH of at least 4 and a maximum of 10.
  • Eudragit for example, an enteric coating based on anionic polymers of methacrylic acid and methacrylates, contains -COOH as a functional group and dissolves in the range of pH 5.5 to pH 7.
  • Shellac or acetylated starch eg Amprac 01
  • the enteric coatings known in the art have various properties (eg pH at which the coating dissolves, dissolution rate), the materials of the coatings can also be combined.
  • Shellac for example, shows a good acid resistance, but dissolves very slowly in the intestinal tract.
  • Amprac 01 dissolves rapidly in the intestinal environment, but does not show sufficient acid resistance.
  • the two above-mentioned materials can be mixed, for example, in a weight ratio of 60-95 / 40-5, preferably 70-90 / 30-10, shellac / Amprac 01.
  • Another parameter influencing the rate of release of the active substance is the layer thickness of the enteric-coated pellet.
  • the layer thickness expressed as a mass ratio, is preferably 5 to 30%, more preferably 10 to 20% of the total mass of the final product.
  • the pellets preferably have an average diameter of 0.5 to 5 mm, in particular 0.7 to 2 mm. Such a size has the advantage that the pellets can pass the stomach quickly.
  • the preparation of the pellets according to the invention which are used both in the pharmaceutical composition according to the invention and in the dietary supplement composition or dietetic food according to the invention, preferably takes place with an extruder which has a thermal stability of the ingredients of the composition, in particular of the active ingredient DAO, from to to 60 ° C is required (Stricker drug form development, Spinger Verlag 2003).
  • the pellets may include, in addition to an enteric coating and the DAO, other pharmaceutical additives.
  • microcrystalline cellulose eg Avicel
  • Cellulose is insoluble in water and has both crystalline and amorphous contents in this form. This combination causes a plastic deformability, that is, at sufficiently high force an irreversible change in shape occurs.
  • microcrystalline cellulose absorbs large amounts of water and is thus without addition of binder to a well compressible, cohesive mass.
  • the amount of microcrystalline cellulose in a pellet may according to the invention be between 5 and 70%, preferably between 10 and 60%, even more preferably between 15 and 50%.
  • sucrose can be used as a binder and filler.
  • Sucrose increases the solubility of the matrix and thus supports the rapid release of the enzyme.
  • sucrose may be added to 1 to 40%, preferably 5 to 35%, more preferably 10 to 30%, of a pellet.
  • Hydroxypropyl cellulose (added in an amount of preferably 0.5 to 10%) may also be added to binders and used to prevent particulate matter. Furthermore, hydroxypropyl cellulose increases the strength of the pellets and thus in turn contributes to improving the yield.
  • Corn starch may be added to the pellet of the invention as a filler and disintegrant (in a preferred amount of from 1 to 30%). As a water-insoluble substance, starch can absorb a lot of water and is therefore an ideal disintegrating agent.
  • Crosscarmellose Na-CMC, Acdisol is a pure disintegrating agent, which can preferably be used in an amount between 1% and 5%.
  • Crosspovidone a cross-linked PVP
  • Povidone is a water-soluble additive and serves as a binding agent. The combination of these different fillers, disintegrants and binders leads to a molecular dispersion of the DAO in the pellet and ensures rapid bioavailability.
  • An insulating layer of glycerol and / or talcum may be provided between the gastro-resistant coating and the pellet containing the active ingredient.
  • Glycerin serves as a humectant to prevent dehydration and thus inactivation of the enzyme.
  • the DAO can also be transported in capsules through the stomach into the intestinal tract.
  • Suitable capsules are e.g. Gelatin capsules or starch capsules.
  • the capsules may also include the pellets of the invention.
  • the diaminooxidase used in the compositions of the invention is non-plant origin.
  • DAOs of non-plant origin in pharmaceutical compositions as well as food supplements and dietetic foods has the advantage that allergens found in plants do not adversely affect the administration of DAO, since allergens substantially promote the body's histamine release. It is known that especially plant substances are responsible for histamine-induced diseases. The complete removal of allergenic ingredients from a DAO preparation of plant origin is possible only with high preparative effort, whereas the DAO according to the invention, which has a non-plant origin completely free of such plant allergens.
  • non-plant origin includes all DAOs which are not derived from plants but from animal organisms or other non-plant organisms. Furthermore fall according to the invention, this definition includes all DAOs which are produced recombinantly in cell cultures (animal, bacterial, yeasts and the like) or in non-plant organisms of any kind, the DNA being used for the recombinantly produced DAO of plant and / or animal organisms by means of known in the art isolated and cloned and expressed in expression systems.
  • compositions disclosed in the present invention comprise diaminooxidase of animal origin.
  • animal DAO By using animal DAO, it is possible to deliver to the human or animal body an enzyme which is very close to the enzyme produced by these individuals in terms of glycosylation, activity and specificity of the DAO itself produced by that individual. Furthermore, it is possible to completely exclude plant allergens from the production of DAO.
  • the diaminooxidase is obtained from pig kidney.
  • Pig kidneys are characterized by their high content of DAO.
  • the enzyme can be isolated in a simple manner by the methods known in the art.
  • compositions according to the invention comprise diaminooxidase of recombinant origin.
  • the recombinant diaminooxidase is expressed in prokaryotic, preferably in bacterial or eukaryotic, preferably in animal or yeast, cell cultures and isolated from the abovementioned expression systems.
  • the purification of DAO produced by these expression systems is accomplished by the methods known in the art. It is also possible to provide the DAO with a peptide (eg His tag), polypeptide or protein sequence (eg GST tag) in order to simplify the purification.
  • the recombinant DAO may further be modified by genetic engineering such that the enzyme activity of this DAO exceeds the enzyme activity of wild-type DAO.
  • a further aspect of the present invention relates to the use of the diaminooxidase according to the invention for the preparation of a medicament for the treatment of histamine-induced clinical pictures.
  • DAO is known to be responsible for the breakdown of histamine in the human and animal body. Since histamine-induced diseases are caused by an excess of histamine due to a lack of diaminooxidase, by inhibition of DAO or by an excess of histamine, usually by food, but also by other extrinsic factors, e.g. Contact with allergens, caused the administration of DAO according to the invention is suitable for the treatment of these diseases or clinical pictures.
  • Another aspect of the present invention relates to the use of the diamine oxidase according to the invention for the manufacture of a medicament for the treatment of urticaria, in particular of chronic and acute urtaria.
  • urticaria In the case of urticaria, release of histamine results in dilation of venules and excessive permeability of the capillaries resulting in edema.
  • DAO diamine oxidase
  • Another aspect of the present invention relates to the use of diaminooxdiase of the invention for the manufacture of a medicament for the treatment of contact allergy.
  • Contact allergies are caused by substances (allergens) that trigger allergic reactions by penetrating the skin.
  • DAO is administered.
  • a diaminooxidase according to the invention is used for the manufacture of a medicament for the treatment of atopic dermatitis.
  • Atopic dermatitis also known as atopic dermatitis, is a common skin condition with severe itching, mostly in children and adolescent adults. The cause of this itching is the excessive release of histamine at the affected skin. In this case, too DAO can contribute to the reduction of histamine in these areas and thus alleviate or prevent the symptoms of atopic dermatitis.
  • the present invention relates to the use of the diaminooxidase of the invention for the manufacture of a medicament for the treatment of scombrotoxism.
  • Scombrotoxismuns is a histamine poisoning after consumption of mackerel species, e.g. of tuna. When the cold chain breaks or the preparation is delayed, scombrids form so-called scombrotoxins, which lead to histamine accumulation. The consequences of this histamine poisoning include fever, nausea, vomiting, abdominal pain and urticaria. DAO can be used as a detoxification agent in this case.
  • a further aspect of the present invention relates to the use of the diaminooxidase according to the invention for the manufacture of a medicament or nutritional supplement or dietetic foodstuff for the removal or reduction of histamine from the gastrointestinal tract.
  • the reduction of histamine from the intestinal tract is of particular importance in an increased supply of histamine (exogenous intake, for example by food) into the body of an individual or, for example, if the activity of DAO in the intestinal tract is partially or completely inhibited.
  • the medicament or dietary supplement or dietetic food according to the invention thus serves for the supply of enzymatically active DAO, which contributes to the breakdown of histamine in the intestinal tract.
  • DAO was actively stabilized in a cellulosic pellet and the pellet was coated with an enteric layer.
  • the dissolution test showed that more than 70% of the activity is released into the environment within the first hour.
  • the enzyme was stabilized in a hydrogel. Storage at room temperature and 37 ° C showed no drop in activity within 4 months. Appearing vesicles and itching on the skin after stimulation with histamine disappeared a few minutes after application of the hydrogel.
  • the action of the hydrogel occurred within the first 10 minutes, with the effect lasting on average more than one hour. 0-10 min 10-30 min 30-60 min > 1h > 3h onset of action 11 1 duration 3 1 2 6
  • hydrogel of the invention works better than a currently used cortisone ointment.
  • Enteric-coated pellets were prepared with 3% DAO having a starting activity of 80,000 U / ml, 40% microcrystalline cellulose, 20% sucrose, 22% other binding, filling and disintegrants and 15% enteric coating.
  • the release of DAO from the pellets was monitored over a period of 180 minutes by means of an activity assay.
  • an activity assay In this case, in the solution in which the pellets were dissolved, already after 10 minutes a DAO activity of 40%, after 30 minutes of 70%, after 60 minutes of 80% and after 180 minutes of 100% of the DAO originally used Amount determined.
  • the activity measurement of the DAO took place as in the AT 411688 However, other known methods can be used to measure the enzyme activity throughout.

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EP05758617A 2004-07-07 2005-07-06 Pharmazeutische zusammensetzungen, die diaminooxidase enthalten Active EP1763363B1 (de)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP07101239A EP1782824B1 (de) 2004-07-07 2005-07-06 Pharmazeutische Zubereitungen als Hydrogel, die Diaminooxidase enthalten
SI200530749T SI1763363T1 (sl) 2004-07-07 2005-07-06 Farmacevtski sestavki, ki vsebujejo diaminooksidazo
AT05758617T ATE432710T1 (de) 2004-07-07 2005-07-06 Pharmazeutische zusammensetzungen, die diaminooxidase enthalten
PL05758617T PL1763363T3 (pl) 2004-07-07 2005-07-06 Kompozycje farmaceutyczne zawierające diaminooksydazę
CY20091100902T CY1109351T1 (el) 2004-07-07 2009-08-28 Φαρμακευτικες συνθεσεις που περιεχουν διαμινοοξειδαση

Applications Claiming Priority (2)

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AT0115004A AT502098B8 (de) 2004-07-07 2004-07-07 Diaminooxidase-hältige zusammensetzung
PCT/EP2005/053234 WO2006003213A1 (de) 2004-07-07 2005-07-06 Pharmazeutische zusammensetzungen, die diaminooxidase enthalten

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US20160024481A1 (en) * 2011-03-18 2016-01-28 Dr Healthcare España, S.L. Topical compositions comprising diaminooxidase for the treatment or prevention of diseases associated with high histamine levels which involve an increase in pain
ES2388515B1 (es) 2011-03-18 2013-10-01 Dr Healthcare España, S. L. Uso de la diaminooxidasa para la prevención de los síntomas de la resaca.
US20170020993A1 (en) * 2011-03-18 2017-01-26 Dr Healthcare España, S.L. Composition comprising diamine oxidase for use in the treatment or prevention of fibromyalgia or chronic fatigue syndrome
ES2387973B1 (es) * 2011-03-18 2013-10-01 Dr Healthcare España, S. L. Composiciones tópicas que contienen diaminooxidasa para el tratamiento o la prevención de enfermedades asociadas a un nivel de histamina elevada que comportan un aumento del dolor.
ES2388166B1 (es) * 2011-03-18 2013-10-01 Dr Healthcare España, S. L. Alimentos funcionales que contienen diaminooxidasa y sus usos.
ES2388395B1 (es) * 2011-03-18 2013-10-01 Dr Healthcare España, S. L. Uso de la diaminooxidasa para el tratamiento o la prevención de la fibromialgia o la fatiga crónica.
WO2012135951A1 (en) 2011-04-07 2012-10-11 Histapharm Inc. Oral enzyme compositions for intestinal delivery
ES2426539B1 (es) 2012-04-18 2014-09-09 Dr Healthcare España, S. L. Uso de la diaminooxidasa para el tratamiento o la prevención del trastorno por deficit de atencion con hiperactividad (adhd)
MX2020007358A (es) * 2017-12-21 2020-09-07 Pepsico Inc Capsula de bebida efimera de multiples ingredientes para preparar una bebida.
KR20210132650A (ko) 2019-02-19 2021-11-04 메디치니쉐 유니베르지테트 빈 신규한 재조합 디아민 옥시다제 및 과잉 히스타민을 특징으로 하는 질환의 치료를 위한 이의 용도

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GB1318884A (en) * 1969-07-29 1973-05-31 Hydrovane Compressor Rotary compressors
FR2101095A1 (en) * 1970-08-20 1972-03-31 Merieux Inst Diamine oxidase from human placenta - for treatment of hyperhistamina
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FR2215944A1 (en) * 1973-02-01 1974-08-30 Bellon Labor Sa Roger Extracts of human placenta - free of proteases, and contg. histaminase, kininases and monoamine-oxidases for treating allergies
FR2529463B1 (fr) * 1982-07-05 1986-01-10 Centre Nat Rech Scient Procede et dispositif pour l'encapsulation dans les erythrocytes d'au moins une substance a activite biologique, notamment des effecteurs allosteriques de l'hemoglobine et erythrocytes ainsi obtenus
GB8319540D0 (en) * 1983-07-20 1983-08-24 Bovril Ltd Amine removal
US4725540A (en) * 1984-07-09 1988-02-16 Emil Underberg Process for the preparation of amine-oxidase containing material, so produced amine-oxidase containing material
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JP4497725B2 (ja) * 1998-11-27 2010-07-07 ▲高▼田 ▲寛▼治 消化管用薬物送達経口製剤
JP4839506B2 (ja) 2000-04-28 2011-12-21 ダイキン工業株式会社 ドライエッチング方法
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IT1317067B1 (it) * 2000-11-29 2003-05-26 Univ Roma Istaminasi di origine vegetale nel trattamento dello shock allergico esettico e nell'asma allergico.
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ATE467423T1 (de) 2010-05-15
DK1763363T3 (da) 2009-09-14
US20100330191A1 (en) 2010-12-30
EP1782824A2 (de) 2007-05-09
AT503070A1 (de) 2007-07-15
EP1782824A3 (de) 2007-07-18
CA2571463C (en) 2014-12-09
AT502098B1 (de) 2007-04-15
MXPA06015036A (es) 2007-04-25
JP2008505869A (ja) 2008-02-28
KR20070032046A (ko) 2007-03-20
CY1109351T1 (el) 2014-07-02
BRPI0513133A (pt) 2008-04-29
SI1763363T1 (sl) 2009-10-31
AT503070B1 (de) 2007-09-15
AU2005259167B2 (en) 2010-06-03
AU2005259167A1 (en) 2006-01-12
JP4959558B2 (ja) 2012-06-27
EP1782824B1 (de) 2010-05-12
BRPI0513133B1 (pt) 2016-12-27
RS51183B (sr) 2010-10-31
KR101367232B1 (ko) 2014-02-25
ES2326421T3 (es) 2009-10-09
HRP20090447T1 (hr) 2009-11-30
PT1763363E (pt) 2009-09-03
WO2006003213A1 (de) 2006-01-12
US8716244B2 (en) 2014-05-06
AT502098A1 (de) 2007-01-15
US20140220148A1 (en) 2014-08-07
ATE432710T1 (de) 2009-06-15
DE502005009568D1 (de) 2010-06-24
PL1763363T3 (pl) 2009-12-31
DE502005007425D1 (de) 2009-07-16
CN1980689A (zh) 2007-06-13
US9364437B2 (en) 2016-06-14
AT502098B8 (de) 2007-06-15
EP1763363A1 (de) 2007-03-21
CA2571463A1 (en) 2006-01-12
US20080193491A1 (en) 2008-08-14

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